Division of Pharmaceutical Sciences, Arnold and Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, 75 Dekalb Avenue, HS Bldg. 612, Brooklyn, NY, 11201, USA.
Kriya Therapeutics, Inc. , 4105 Hopson Rd, Morrisville, NC, 27560, USA.
AAPS PharmSciTech. 2024 Nov 19;25(8):270. doi: 10.1208/s12249-024-02979-4.
A method is presented for determining the thermodynamic (equilibrium) solubility of a drug in coformer for the non-covalent derivative (NCD) systems i.e. eutectics/co-crystals. The method is based on a thermodynamic model to calculate the Gibbs energy change ∆G associated with forming a drug-coformer NCD system. This model includes contributions from heat capacity differences between the mixed and unmixed components, breaking up of the solid drug and coformer lattice structure, and drug ─ coformer mixing. Calculation of ∆G from thermal analysis data is demonstrated, and the equilibrium drug solubility in coformer is represented by minima of plots of ∆G versus the dissolved drug fraction (f). Eight (8) coformer molecules, namely, 1-hydroxy 2-naphthoic acid (1H-2NPH), 4-hydroxy benzoic acid (4-HBA), salicylic acid (SLC), 4-amino salicylic acid (4-ASA), 5-nitro isophthalic acid (5N-IPH), pyrazinamide (PZD), isonicotinamide (ISNCT), and picolinamide (PICO) were used for the formation of NCDs of a highly water insoluble drug febuxostat (FXT). The importance of heat capacity and interaction parameter in determining the solubility behavior of drug-coformer in the formed NCDs was discussed. Further, ∆G for FXT in selected NCDs were plotted as a function of composition and temperature to determine the thermodynamic stability over the range of room temperature to formulation melting. It was concluded that the thermodynamic model can reasonably predict the maximum stable drug loading in a multi-crystalline system at a particular temperature, and serve as a complementary screening tool in determining the best stoichiometric ratio of the drug and coformer in terms of solubility and thermodynamic stability.
介绍了一种用于确定非共价衍生物（NCD）体系即共晶/共晶体中药物共晶形成剂热力学（平衡）溶解度的方法。该方法基于计算与形成药物-共晶形成剂 NCD 系统相关的吉布斯能变化 ∆G 的热力学模型。该模型包括混合和未混合成分之间热容差、药物和共晶形成剂晶格结构的破坏以及药物-共晶形成剂混合的贡献。通过热分析数据计算 ∆G，并通过 ∆G 与溶解药物分数（f）的关系图的最小值来表示共晶形成剂中的平衡药物溶解度。使用了八种（8）共晶形成剂分子，即 1-羟基 2-萘甲酸（1H-2NPH）、4-羟基苯甲酸（4-HBA）、水杨酸（SLC）、4-氨基水杨酸（4-ASA）、5-硝基间苯二甲酸（5N-IPH）、吡嗪酰胺（PZD）、异烟酰胺（ISNCT）和吡啶酰胺（PICO），用于形成高度水溶性差的药物非布索坦（FXT）的 NCD。讨论了热容量和相互作用参数在确定形成的 NCD 中药物-共晶形成剂的溶解度行为中的重要性。此外，还将选定的 NCD 中 FXT 的 ∆G 作为组成和温度的函数进行了绘制，以确定在室温至制剂熔融范围内的热力学稳定性。得出的结论是，热力学模型可以合理地预测特定温度下多晶体系中最大稳定药物载药量，并作为确定药物和共晶形成剂在溶解度和热力学稳定性方面最佳化学计量比的补充筛选工具。
